Contemporary literature shows considerable interest in derivatives of barbituric acids due to their influence on various enzyme systems [2—Novac L., Kovac B. Electronic structure and biological activity: barbiturates end thiobarbiturates//Shem. Phys. Lett. 2010, 493, 242-244]. Of particular interest are 5-arylidene derivatives of barbituric acids that have anticonvulsant, antimicrobial, spasmolytic, antipyretic and antineoplastic activity [3—Sans R. G., Chosas M. G.//Pharmazie, 1988, Bd 43, N 12, S. 827-829]. New publications appear that study antibacterial properties of 5-arylidene barbituric acids [4—Yan Q., Cao R., Yi W., Shen Z., Wen H., Ma L., Song H.//Inhibitory effects of 5-arylidene barbiturate derivatives on mushroom tyrozinase and their antibacterial activity//Eur. J. Med. Chem., 2009, 44, 4235-4243].
Earlier many other 5-arylidene barbituric acids have been discovered to have valuable biological properties—pesticide, antineoplastic, antimicrobial, immunosuppressive, nootropic, antihypertensive and antiallergic [5—Singh A., Mohan R. R., Misra V. S.//Indian Drugs., 1985, Vol. 22, N 8, P. 418-422 (Chemical Abstracts, Vol. 104, 129855c).
6—Singh S., Gupta G. P., Shanker K.//Indian J. Chem., 1985, Vol. 24B, N 10, P. 1094-1097.
7—Singh A., Misra V. S.//Pharmacol. Res., 1989, Vol. 21, N 1, P. 59-64 (Chemical Abstracts, Vol. 111, 49906z).
8—Kumar P., Nath C., Agarwal J. C., Bhargava K. P., Shanker K.//Indian J. Chem., 1983, Vol. 22B, N 9, P. 955-958.
9—patent of Japan, international classifier A 61K 31/505, No 05213755, pending since Jul. 2, 1992 (92/56671), published on 24 Aug. 1993 (Chemical Abstracts, 1993, Vol. 119, 262520r).
10—Kumar A., Singh S., Saxena A. K., Shanker K.//Indian J. Chem., Sect. 1988, Vol. 27, N 5, P. 443-447.
11—Hirota K., Fukazawa T., Isobe Y., Morita H., European Patent Office application No. 546661 in international classifier. S 07D 239/62, pending since Sep. 10, 1991 (91/290538), published on 16 Jun. 1993 (Chemical Abstracts, Vol. 119. 180814a).
The abovementioned references indicate that the search for new antibacterial agents among barbituric acids, in particular among 5-arylidene derivatives of barbituric acid, has good potential.
High variability of bacteria that results in the emergence and fast propagation of antibiotic resistance among bacteria does not allow achieving significant clinical results in treatment of a large number of diseases of different localizations caused by said bacteria. Medicine needs new drugs that have no analogues and consequently do not have resistant clones circulating around. The discovered peculiarities of microbial activity in biofilms have shown the necessity of selecting antimicrobial drugs with new properties.
Staphylococcus aureus is arguably the most problematic pathogen faced by modern healthcare systems today, owing in large part to the persistent emergence of antibiotic resistant strains. This is perhaps most evident in the recent appearance of methicillin-resistant strains even among isolates causing community-acquired infection. Moreover, many of these strains have the capacity to cause serious, life-threatening infection even in otherwise healthy individuals. This accounts in large part for the observation that, in the United States alone an estimated more than 100,000 patients suffered from invasive infection caused by Methicillin-resistant Staphylococcus aureus (MRSA) [http://www.ndhealth.gov/disease/Documents/Resources/MRSA%20Book/MRSAVRE.pdf], with approximately 20,000 resulting in a fatal outcome. The continued emergence of antibiotic-resistant strains has created an urgent need for new antimicrobial agents.
Ampicillin antibiotic was selected as the prototype of the current invention, since its biological effect has the greatest similarity to the inventive agent. Ampicillins inhibit one of the enzymes involved in the synthesis of the bacterial cell walls. The loss of the stability conferred by the wall leads to the cell lysing.
Ampicillin is represented as the following compound:
6-[[(2R)-aminophenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2carboxylic acid, see: [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6249].
Ampicillin is a broad spectrum antibiotic, but it has no effect on Methycillin Resistant Staphylococcus aureus (MRSA) mycobacteria and fungi, and has poor penetration rate into bacterial biofilms [Davies D. Understanding biofilm resistance to antibacterial agents. Nat Rev Drug Discov 2003; 2:114-122; Anderl, J. N., Franklin M. J., Stewart P. S. Role of antibiotic penetration limitation in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin. Antimicrob. Agents Chemother. 2000. 44:1818-1824.]